The cytokine, interleukin-15 (IL-15), a member of the four alpha-helix bundle family of lymphokines, plays a pivotal role in modulating the activity of both the innate and adaptive immune system, e.g., expansion and maintenance of the memory T-cell response to invading pathogens, and induction of Natural Killer (NK) cell proliferation and cytotoxic activity.
The IL-15 receptor consists of two polypeptides, the IL-2/IL-15 receptor beta (“β”) (or CD122), and the gamma chain (“γ”) (or CD132) that is shared by multiple cytokine receptors. IL-15 signaling has been shown to occur through the heterodimeric complex of IL-15Rβ and IL-15Rγ. Despite existing theories suggesting that IL-15Rα is a receptor for IL-15, an alternative interpretation of the existing data is that IL-15Rα is not a receptor for the IL-15 polypeptide chain. IL-15Rα has evolved very high affinity for IL-15 and is always co-expressed with IL-15 in the same cell. The two molecules form heterodimeric complexes in the Endoplasmic Reticulum and are transported to the plasma membrane. See, e.g., Bergamaschi et al., 2012, Blood 120: e1-e8. This heterodimeric complex can bind to the IL-2/IL-15βγ receptor and activate the cells via the Jak/Stat pathway. Therefore, based upon this interpretation of the data, the IL-15Rα and the soluble form sIL-15Rα are part of the cytokine and not part of the receptor. Id.
IL-15 specifically binds to the IL-15Rα with high affinity via the “sushi domain” in exon 2 of the extracellular domain of the receptor. Endogenous heterodimeric IL-15 is found in two forms, as a membrane-bound form that is expressed by antigen presenting and stroma cells in various tissues; and as a soluble extracellular complex of IL-15 to the soluble IL-15Rα, which is produced by cleavage of the membrane-anchored IL-15Rα by cellular proteases. Although IL-15 mRNA has been reported in cells of both hematopoietic and non-hematopoietic lineage, T cells do not produce IL-15. Instead, IL-15 heterodimers released from the cell surface after cleavage of the membrane bound heterodimers binds to the IL-15βγ Receptor on lymphocytes.
Based on its multifaceted role in the immune system, various therapies designed to modulate IL-15-mediated function have been explored. For example, the administration of exogenous IL-15 can enhance the immune function of patients infected with human immunodeficiency virus (HIV). In keeping with its immune enhancing activity, increased expression of endogenous IL-15 is observed in patients with autoimmune diseases, e.g., rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and psoriasis. Because some studies reported that the soluble form of the IL-15Rα (sIL-15Rα) is an antagonist of IL-15-mediated signaling, the sIL-15Rα has been explored for treating autoimmune inflammatory diseases. Nevertheless, recent reports suggest that IL-15, when complexed with the sIL-15Rα, or the sushi domain, maintains its immune enhancing function.
Despite the amount of progress made in understanding the function of IL-15, it is unclear how various forms of the IL-15Rα, alone or when complexed to IL-15, can be used to modulate IL-15 function as part of a therapeutic regimen.